Ischemic brain injury causes death and long-term disability in patients who suffer cardiac arrest and embolism stroke in the United States and in our VA community. Ischemia-induced neuronal hyperactivity in the affected neurons is a key step in the development of neurodegeneration as it leads to cell death, irreversible loss and reorganization of neuronal circuits, and eventually neuronal deficiency. Immediately after Ischemia, cell membrane depolarization, excess glutamate secretion, overactivity of ionotropic glutamate receptor, and loss of GABA signaling are thought to cause neuronal hyperactivity. GABA-B-Rs (R1 and R2) are members of the family C of the G-protein coupled receptor (GPCR) superfamily, which also includes the extracellular Ca2+- sensing receptor (CaSR). GABA-B-Rs generally function in the form of heterodimer comprised of GABA-B-R1 and GABA-B-R2 subunit that is required for stable cell-surface expression and signaling of the receptor complex to produce inhibitory neuronal input and prevent neuronal overactivity. The GABA-B-Rs and the CaSR are co-expressed in many regions of the brain, including hippocampus. Unlike the GABA-B-R1/R2 heterodimer, the CaSR can function in the form of homodimer to exert excitatory signaling responses -- activation of Ca2+ and non-selective cation channels, stimulation of phospholipase C, increases in [Ca2+]i, and increasing cell excitability in neurons and other cell systems. GABA-B-R1 can heterodimerize with CaSR and suppress the total and cell-surface expression of CaSR protein and its signaling responses in transfected HEK- 293 cells. Contrarily, knocking out GABA-B-R1 gene in hippocampal neurons up-regulates CaSR expression. We further observed CaSR overexpression in ischemic hippocampal neurons, which showed reduced GABA- B-R1 expression, suggesting a counteracting interaction between the CaSR and GABA-B-R1 expression. The increased expression and activity of CaSR could contribute to the hyperactivity of the ischemic neurons via its own excitatory actions and/or its ability to interfere with the formation of GABA-B-R1/R2 heterodimers, therefore reducing GABA responses. In supporting the latter notion, we found that in the HippCaSR-KO mice, which have their CaSR genes deleted in hippocampal neurons, ischemia no longer inhibited the GABA-B-R1 expression or caused cell death. We hypothesize that ischemia-induced CaSR overexpression causes neuronal hyperactivity and cell death by stimulating CaSR-mediated signaling responses and by inhibiting GABA-B-R1 expression via stoichiometric competition for binding to GABA-B-R2, and that blocking the expression or activity of CaSR together with enhancement of GABA-B-R signaling are required for optimal neuroprotection against ischemic injuries. Our proposal will (1) determine whether deleting CaSR gene or blocking CaSR activity by specific antagonists (or calcilytics) protects against the ischemia-induced neuronal injury and blunts the inhibitory effect of ischemia on the expression, trafficking, and dimerization of GABA-B-R1/R2 and (2) determine whether sustaining GABA-B-R1 expression is required for neuroprotection against cerebral ischemia and whether a combined therapy with calcilytics and GABA-B-R1 agonists further enhances neuroprotection against ischemia-induced brain injury. The successful completion of the study will establish a novel pathway that produces ischemia-induced neuronal injury and will develop a new therapy for treating diseases due to ischemic brain injury.